Mechanistic and Pharmacokinetic Studies of Classical Chinese Formula Xiao Chai Hu Tang Against Irinotecan-Induced Gut Toxicities

中药方剂小柴胡汤抗伊立替康肠道毒性的机制和药代动力学研究

• 批准号: 10262912
• 负责人: MING HU
• 金额: $ 19.69万
• 依托单位: UNIVERSITY OF HOUSTON
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-11 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10262912
• 关键词: Animals; Antidiarrheals; Antineoplastic Agents; Atrophic; Attenuated; Bacteria; Beta-glucuronidase; Biliary; Biological Products; Cessation of life; Chai Hu; Chinese People; Chinese Traditional Medicine; Clinical; Clinical Research; Clinical Trials; Cyclosporine; Diarrhea; Dose; Double-Blind Method; Down-Regulation; Drug Exposure; Drug Kinetics; Drug Metabolic Detoxication; Drug resistance; Enzyme Activation; Enzymes; Excretory function; GTP-Binding Protein alpha Subunits, Gs; Glucuronides; Glucuronosyltransferase; Goals; Hospitalization; Human; In Vitro; Incidence; Inflammation; Inflammatory; Intestines; Investigational Therapies; Lead; Life; Malignant Neoplasms; Malignant neoplasm of pancreas; Medical; Methods; Modeling; Mucositis; Mus; Natural Products; Pathway interactions; Patients; Pharmaceutical Preparations; Phase II Clinical Trials; Phytochemical; Plasma; Prevention; Prodrugs; Quality Control; Quality of life; Raloxifene; Randomized; Recovery; Research; Resort; Running; SN-38; SN-38G; Safety; Signal Transduction; Testing; Therapeutic; Tight Junctions; Tissues; Toll-like receptors; Toxic effect; Treatment Efficacy; Treatment outcome; Villus; attenuation; cancer care; cancer therapy; chemotherapeutic agent; chemotherapy; cytokine; design; dietary supplements; experience; functional restoration; improved; in vivo Model; irinotecan; malignant stomach neoplasm; metastatic colorectal; novel; novel strategies; pharmacokinetics and pharmacodynamics; preservation; prevent; primary outcome; receptor; refractory cancer; response; secondary endpoint; side effect; success; targeted agent

Abstract Irinotecan, a prodrug of SN-38, is used to treat many types of metastatic and drug-resistant cancers, and often represents the therapy of the last resort. Unfortunately, a large percentage (up to 40%) of these patients will experience serious (Grade 2) and severe (Grade 3-4) delayed-onset diarrhea (SDOD), which really downgrade patient’s quality of life. SDOD may lead to prolonged hospitalization and even death in some instances. The long-term goal of our research is to develop experimental therapeutics and/or nutritional supplemental approach to reduce SDOD, so patients can sustain their chemotherapy. Our recent studies have shown that inactivation of intestinal UDP-glucuronosyltransferases (UGTs) by SN-38 is a new mechanism by which SN-38 causes SDOD, and that a Traditional Chinese Medicine, Xiao-Chai-Hu-Tang (XCHT), could attenuate the inactivation of intestinal UGTs in mice. Therefore, the central hypothesis of this current proposal is Therefore, we hypothesize that XCHT will prevent or reduce irinotecan-induced SDOD by attenuating the decline in UGT activities, reducing gut SN-38 exposure, and promoting the recovery of gut UGT activities. We plan to test this hypothesis using four Specific Aims: (1) perform phytochemical, biopharmaceutical and pharmacokinetic characterization of XCHT to enable quality control, systemic and intestinal drug exposure determinations, and to provide bioanalytical methods and pharmacokinetic parameters needed for a clinical study and PK/PD modeling; (2) validate plasma raloxifene-4′-glucuronide levels as a probe to changes in intestinal Ugt/UGT activity; (3) Perform mouse “co- trial” studies to support human mechanistic trials and to determine the mechanisms of action of XCHT against irinotecan-induced SDOD using both in vitro and in vivo models; and (4) Conduct a mechanistic clinical trial using a randomized double-blind design with a safety “Run-In” to determine if XCHT can attenuate human intestinal UGT decrease and reduce incidence of Grade 3 or higher diarrhea caused by irinotecan chemotherapy. Aside from these primary outcomes, we will also determine if levels of Ral-4’-G, a probe of intestinal UGT activities is (negatively) correlated with systemic levels of inflammatory cytokines. Success gained through this research will provide a new mechanism by which we can target to treat SDOD caused by irinotecan chemotherapy.

摘要 伊立替康是SN-38的前药，用于治疗许多类型的转移性和耐药性癌症，并且通常与其他药物一起使用。 是最后的治疗手段不幸的是，这些患者中有很大一部分（高达40%）将 发生严重（2级）和严重（3-4级）迟发性腹泻（SDOD）， 患者的生活质量。SDOD可能导致住院时间延长，在某些情况下甚至死亡。的 我们研究的长期目标是开发实验性治疗和/或营养补充方法 以减少SDOD，使患者能够持续化疗。我们最近的研究表明， 肠UDP-葡萄糖醛酸基转移酶（UGT）的SN-38是一种新的机制，SN-38导致 中药小柴胡汤（XCHT）能减弱SDOD的失活， 小鼠肠道UGT。因此，当前提案的中心假设是， XCHT将通过减弱UGT活性的下降，降低 肠道SN-38暴露，并促进肠道UGT活性的恢复。我们计划用四个例子来验证这个假设。 具体目的：（1）进行XCHT的植物化学，生物制药和药代动力学表征， 能够进行质量控制、全身和肠道药物暴露测定，并提供生物分析 临床研究和PK/PD建模所需的方法和药代动力学参数;（2）验证血浆 雷洛昔芬-4 ′-葡萄糖醛酸苷水平作为肠道Ugt/UGT活性变化的探针;（3）进行小鼠“co- 试验”研究，以支持人体机制试验，并确定XCHT的作用机制， 使用体外和体内模型进行伊立替康诱导的SDOD;和（4）使用 一项随机双盲设计，具有安全性“导入”，以确定XCHT是否可以减弱人肠道 UGT减少和降低伊立替康化疗引起的3级或以上腹泻的发生率。一边 从这些主要结果中，我们还将确定Ral-4 '-G（肠道UGT活性的探针）的水平是否 与全身炎症细胞因子水平呈负相关。通过这项研究取得的成功将 为靶向治疗伊立替康化疗引起的SDOD提供了新的机制。